Paroxetine cholate or cholic acid derivative salts, and composition comprising paroxetine and cholic acid or derivative thereof

ABSTRACT

Disclosed herein is a paroxetine cholate or cholic acid derivative salt and a composition comprising paroxetine and cholic acid or a derivative thereof. Further disclosed is a pharmaceutical composition comprising the paroxetine salt or the composition. The pharmaceutical composition can be formulated into an oral preparation for swallowing without water as an orally disintegrating tablet for paroxetine.

TECHNICAL FIELD

The present invention relates to paroxetine cholate or cholic acidderivative salts, and a composition comprising paroxetine and cholicacid or a derivative thereof.

BACKGROUND ART

Paroxetine has the chemical formula(−)-(3S,4R)-4-(p-fluorophenyl)-3-[(3,4-methylenedioxy)phenoxy]-methyl]piperidine,and is used as a therapeutic agent for the treatment of depression,panic disorder, pre-menstrual dysphoric disorder and social phobia bytaking advantage of a typical selective serotonin (5-HT) reuptakeinhibitor (SSRI) mechanism.

It is reported that since general anti-depressants, includingparoxetine, have poor medication compliance in patients, the developmentof oral formulations for swallowing without water will improve themedication compliance of patients by decreasing the sensation ofmedicine administration. According to clinical results of Remeron SolTab(manufactured under the trade name Mirtazapine by Janssen), which is thefirst developed oral anti-depressant for swallowing without water in theworld, continuous treatment of depression without stopping in theinitial stage is mentioned as a critical factor in the improvement ofsymptoms in a depressive patient. A study on patients who had beenadministered Remeron SolTab reported that the patients preferred SolTabpreparations to other conventional pills. This study also reported thatthe proportion of patients responding the selection of SolTab is sixtimes higher than that responding the selection of other pills. Theseresults reveal that the use of anti-depressants for swallowing withoutwater improves therapeutic compliance in patients and thus betterresults in the treatment of depression and the prevention of depressionrecurrence can be expected.

However, paroxetine has a very bitter taste even at low concentrations,whilst it causes irritating pain along with a very bitter taste at highconcentrations due to its inherent characteristics. Accordingly,paroxetine is limited in its ability to be developed into solid oralformulations for swallowing without water. Although paroxetine can becoated with or included in materials, such as polymers andcyclodextrins, by common techniques known in the art, the bitter tasteof paroxetine is incompletely masked. Particularly, when paroxetine isformulated into a tablet, the shape of the coated or included granulemay be partially collapsed to expose the contents to the outside of thegranule, which render an uncomfortable sensation in the mouth. In orderto wholly or partially block the bitter and irritant taste ofparoxetine, the use of excipients in large quantities is necessary.Accordingly, it is substantially impossible to develop an orallydisintegrating tablet.

PCT Publication WO 95/020964 discloses a process for formulating aliquid preparation (liquid for medication) by dispersing awater-insoluble ion exchange resin in water and formulating thedispersion with a drug, thereby masking the bitter taste of the drug.However, since the ion exchange resin is insoluble in water, it cannotbe uniformly distributed in an aqueous phase and thus the bitter tasteof the drug cannot be completely masked.

In efforts for masking the inherent taste of paroxetine with anothertaste, glycyrrhyzinic acid or glycyrrhyzinate salts are found in PCTPublications WO 03/013470 and WO 03/013529. These publications mentionthat since glycyrrhyzinate as a main ingredient of liquorice has itselfan intense flavor of sweet liquorice, it can contribute to masking thebitter taste of paroxetine. In fact, the abstracts of the publicationsdescribe that because of the intensity of liquorice flavor even in astate where glycyrrhyzinate is formulated, further flavorings may bedesirable to modify the liquorice taste of the formulation.

A number of studies on salts of paroxetine have been activelyundertaken. For example, U.S. Pat. No. 4,721,723 and PCT Publication WO99/32484 describe paroxetine hydrochloride; PCT Publication WO 99/52901describes paroxetine maleate; PCT Publication WO 99/55699 describesparoxetine camphorsulfonates; PCT Publication WO 99/55698 describesparoxetine ascorbate; PCT Publication WO 00/01694 describes paroxetinemethanesulfonate; PCT Publications WO 03/013470 and WO 03/013529describe glycyrrhyzinate or glycyrrhyzinate salts; PCT Publication WO99/40084 describes salts of paroxetine with acids, including sulfuric,tartaric, oxalic, fumaric, propionic, formic, glutamic, succinic,benzoic, citric, nitric, phosphoric, 4-methylbenzenesulfonic,hypophosphorous, lactic, and mandelic acids, without detailedexplanations regarding the salts; and PCT Publication WO 00/01692describes salts of paroxetine with an acid group. However, none of theabove patent publications mention an improvement in taste associatedwith the use of the paroxetine salts.

In addition to these salts of paroxetine, PCT Publication WO 95/20964claims a liquid oral preparation using a paroxetine-amberlite complex.However, the amberlite resin is not a monomolecular material, but apolymeric material carrying many charges in a single molecule, and isparticularly insoluble in water or solvents. The molecular weight ofpolymers can be expressed only by average molecular weight due to thecharacteristics of polymers. Accordingly, the binding molar ratio of theamberlite resin to the drug cannot be precisely attained, unlikemonomolecular salts, and thus it is difficult to say that theparoxetine-amberlite complex is a salt. In addition, the taste-maskingeffects of the polymeric resin are due to the dispersion of thewater-insoluble resin-drug complex in water. Accordingly, the effects ofthe complex are distinguished from those of paroxetine salts.

Little has heretofore been reported, suggested, or experimentally provedabout the absence of taste and pain of paroxetine, and the greatlyimproved stability of paroxetine through the formation of paroxetinesalts. Particularly, there are no reports about paroxetine cholate andcholic acid derivative salts.

Thus, it is an object of the present invention to provide a paroxetinesalt or a paroxetine composition capable of causing changes in thecharacteristics of paroxetine molecular units to change the tasteproperties of paroxetine such that the bitter taste of paroxetine, evenafter it is completely dissolved in water, is removed in the salt or thecomposition.

It is another object of the present invention to provide a paroxetineoral preparation for swallowing without water, namely an orallydisintegrating tablet, comprising the paroxetine salt or the paroxetinecomposition.

DISCLOSURE OF THE INVENTION

In accordance with one aspect of the present invention, there isprovided a paroxetine cholate or cholic acid derivative salt. Theparoxetine cholate salt is particularly preferred.

In accordance with another aspect of the present invention, there isprovided a composition comprising paroxetine and cholic acid or aderivative thereof.

Cholic acid and its derivatives are represented by Formula 1:

wherein R₁, R₂, and R₃ are independently hydrogen or a hydroxy group;and X is —OH, —ONa, —NH—(CH₂)_(n)—SO₃H, —NH—(CH₂)_(n)—SO₃Na,—NH—(CH₂)_(n)—SO₃K, —NH—(CH₂)_(n)—CO₂H, —NH—(CH₂)_(n)—CO₂Na, or—NH—(CH₂)_(n)—CO₂K (in which n is an integer between 1 and 3),

or Formula 2:

wherein X is as defined in Formula 1.

Cholic acid of the present invention has the chemical formula3α,7α,12α-trihydroxycholan-24-oic acid, and is also termed ox bileextract, cholalic acid, cholalin or cholanic acid.

Examples of suitable cholic acid derivatives of the present inventioninclude 3α,12α-dihydroxycholan-24-oic acid (deoxycholic acid),3,7,12-trioxocholan-24-oic acid (dehydrocholic acid),3α,7α-dihydroxycholan-24-oic acid (chenodeoxycholic acid),3α,7β-dihydroxycholan-24-oic acid (ursodesoxycholic acid),3α-hydroxycholan-24-oic acid (lithocholic acid),2-[(3α,7α,12α-trihydroxy-24-oxocholan-24-yl)amino]ethanesulfonic acid(taurocholic acid), 2-(3α,7α,12α-trihydroxy-24-oxocholan-24-yl)glycine(glycocholic acid), and so on. Alkali metal salts and other derivativesthat can be prepared from these cholic acid derivatives are also withinthe scope of the present invention. These cholic acid derivatives have asteroid structure as a common mother nucleus, and belong to steroidacids containing a carboxyl group. Acidic materials having a steroidmother nucleus which can be extracted from the bile of humans andanimals, and salts with alkali metal ions thereof are also within thescope of the present invention.

Cholic acid and its derivatives produced in a living body are well knownas main ingredients of bile secreted into the intestinal tract andreabsorbed in a volume of 500 mL daily. About 20 g to about 30 g ofcholic acid and its derivatives, on a dry mass basis, are contained inthe daily volume (500 mL) of the bile secreted into the upper part ofthe small intestine, among which about 0.5 g is discharged in the formof excrement in the course of intestinal re-absorption. About 400 mg isproduced by the body each day to compensate for the loss. Accordingly,when the paroxetine cholate or cholic acid derivative salt of thepresent invention is administrated orally to treat depression in humans,the amount of cholic acid or its derivatives is limited to a maximum of40 mg per day on a routine basis. Since the dose range of cholic acid orits derivatives by the paroxetine salt above, corresponds to about 0.13%to 0.2% of the total amount of circulating bile in human intestines,toxicity and side effects cannot be considered. Therefore, cholic acidand its derivatives are very suitable as salts of drugs. Particularly,cholic acid or ox bile extract is currently used as an emulsifier forfoods in Japan, and is classified on the generally recognized as safe(GRAS) list by the FDA in the United States.

The paroxetine cholate or cholic acid derivative salt according to thepresent invention is in crystalline, non-crystalline or polycrystallineform. The crystalline or non-crystalline form is preferred. In thepreparation of the paroxetine cholate or cholic acid derivative salt,the molar ratio of cholic acid or a derivative thereof to paroxetine inthe form of free base is between 0.25:1 and 5:1, and preferably between0.5:1 and 2:1.

The paroxetine cholate or cholic acid derivative salt according to thepresent invention can be prepared in accordance with the followingprocedure.

The paroxetine cholate or cholic acid derivative salt can be prepared bysimply contacting the paroxetine free base with cholic acid or aderivative thereof in a given molar ratio. At this time, it is preferredthat the free base is in a solution phase. More preferably, both thefree base and the cholic acid or its derivative are in a solution phase.Specially, the paroxetine cholate or cholic acid derivative salt can beprepared by dissolving the paroxetine free base in an appropriatesolvent and then, dissolving cholic acid or a derivative thereof in thesolution; or by dissolving cholic acid or a derivative thereof in anappropriate solvent separately and then, mixing the obtained solutionwith a solution of the paroxetine free base previously dissolved.

The paroxetine used to prepare the salt may be in an oily free base formin which a salt portion is removed from a paroxetine salt, or aparoxetine salt itself. In the case where a paroxetine salt is useddirectly, it is advantageous in terms of effective separation andpurification that a salt portion is volatile or highly soluble insolvents.

Suitable solvents used to prepare the salt are not specificallyrestricted so long as they can easily dissolve the free base. Also thesolvents can be used to dissolve the cholic acid or its derivative.Examples of suitable solvents include water, and organic solvents, e.g.,methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methylacetate, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone,methyl isobutyl ketone, toluene, tetrahydrofuran, 1,4-dioxane,dimethoxyethane, dichloromethane, dichloroethane and ethyl ether. Thesesolvents may be used alone or in combination of two or more solvents.The removal of the solvent used can be carried out by general processes,e.g., drying under reduced pressure or vacuum, volatilization, spraydrying, lyophilization (freeze drying), cooling filtration, andcombinations thereof, to prepare a solid crystalline, non-crystalline,or polycrystalline paroxetine cholate or cholic acid derivative salt.Drying under reduced pressure or vacuum, volatilization, and coolingfiltration are preferably employed to prepare a crystalline paroxetinesalt. Meanwhile, spray drying and lyophilization are preferably used toprepare a non-crystalline paroxetine salt.

To prepare the salt in a solid state in the presence of the solvent,first, paroxetine and the cholic acid or its derivative are dissolved inthe single or mixed solvent. Thereafter, the obtained solution isallowed to stand under the temperature of 0° C., or another solvent ismixed with the solution to precipitate the paroxetine salt. Theprecipitate is filtered, washed with a cold solvent, and dried to affordthe final paroxetine cholate or cholic acid derivative salt. The coldsolvent used herein is selected from solvents which can be mixed withthe single or mixed solvent but cannot readily dissolve the finalparoxetine cholate or cholic acid derivative salt.

The paroxetine salt thus prepared may be obtained in anhydride orhydrate form. If the paroxetine salt is obtained in a solvate form,volatilization of intermolecular solvent is carried out in a dry oven orsolvent displacement is carried out to remove the solvate.

For the purpose of improving the yield of the paroxetine cholate orcholic acid derivative salt, heating can be performed to increase theconcentrations of the free base and the cholic acid or its derivative inthe solution. Alternatively, the free base and the cholic acid or itsderivative are dissolved in an appropriate solvent, and then a portionof the solvent can be removed by drying under vacuum or volatilization.Also, a crystal seed can be added to promote the precipitation of theparoxetine salt.

The present invention also provides a composition comprising paroxetineand cholic acid or a derivative thereof.

Although the paroxetine in free base or salt form is brought intocontact with the cholic acid or its derivative in a specific molar ratiowith or without water or an organic solvent, if complete or partialchanges in the physical properties of the resulting salt, which reducethe taste or pain associated with paroxetine, are involved, those alsofall within the scope of the present invention.

In the preparation of the composition according to the presentinvention, the molar ratio of the cholic acid or its derivative to theparoxetine free base is between 0.25:1 and 5:1, and preferably between0.5:1 and 2:1. The composition of the present invention can be preparedby uniformly blending paroxetine and cholic acid or a derivative thereofin water or an organic solvent, followed by drying. The solvent used toprepare the composition of the present invention is identical to thatused to prepare the paroxetine salt.

The present invention can provide a pharmaceutical compositioncomprising the paroxetine cholate or cholic acid derivative salt and apharmaceutically acceptable excipient. The present invention alsoprovides a pharmaceutical composition comprising paroxetine, cholic acidor a derivative thereof, and a pharmaceutically acceptable excipient.The pharmaceutical compositions of the present invention can beformulated into oral preparations for swallowing without water. Apharmaceutical composition comprising the paroxetine salt and theparoxetine composition (including paroxetine, cholic acid or aderivative thereof) is also within the scope of the present invention.

The pharmaceutically acceptable excipient can be at least one selectedfrom diluents, binders, disintegrants, coloring agents, sweeteningagents, flavors, preservatives, lubricants, and so on. Excipients havingcomposite functions may be also used. Particularly, the pharmaceuticallyacceptable excipient can be at least one agent selected from excipientshaving natures of diluents and disintegrants and showing rapiddisintegration properties, e.g., the products sold under the trade namesPharmaburst and Pharmagum. The diluent can be at least one selected fromlactose, dextrose, microcrystalline cellulose, starch, and so on; thebinder can be at least one selected from polyvinyl pyrrolidone,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, dicalcium phosphate, sodium alginate, and so on; thedisintegrant can be at least one selected from sodium croscarmellose,sodium starch glycolate, crosslinked polyvinyl pyrrolidone, gelatinizedstarch, low-substituted hydroxypropyl cellulose, and so on; the coloringagent can be at least one selected from water-soluble colorants, tarcolorants, and so on; the sweetening agent can be at least one selectedfrom dextrose, sorbitol, mannitol, aspartame, acesulfame, citric acid,and so on; the flavor can be at least one selected from orange, grape,strawberry, blueberry flavor powders, and so on; the preservative can beat least one selected from benzoic acid, methyl paraben, ethyl paraben,propyl paraben, and so on; and the lubricant can be at least oneselected from magnesium stearate, talc, hard anhydrous silica, sucrosefatty acid esters, and so on.

The pharmaceutical composition of the present invention can beformulated by conventional pharmaceutically approved techniques, e.g.,blending, kneading, sieving, filling, and compressing.

The pharmaceutical composition of the present invention may beformulated into ordinary dosage forms, for example: solid oralpreparations, such as tablets, capsules, granules, and powders; andliquid oral preparations, such as syrups; suppositories; and vialinjections. Tablets, capsules and syrups for oral administration arepreferred.

The pharmaceutical composition of the present invention may beadministered by any convenient route, e.g., orally, sublingually,buccally, rectally, transdermally, parenterally, intravenously,intramuscularly, etc. Oral, sublingual, and buccal administrations aresuitable for the object of the present invention because they allow thecomposition to be dissolved or swallowed in the mouth without water.

The pharmaceutical composition of the present invention can beadministered for the treatment of depressive disorder in such an amountthat the content of paroxetine is 20˜50 mg/day; in such an amount thatthe content of paroxetine is 40 mg/day up to a maximum of 60 mg/day,initiating from 20 mg/day, for the treatment of obsessive-compulsivedisorder; in such an amount that the content of paroxetine is 40 mg/dayup to a maximum of 50 mg/day, initiating from 10 mg/day, for thetreatment of panic disorder; in such an amount that the content ofparoxetine is up to a maximum of 50 mg/day, initiating from 20 mg/day,if needed, increasing at a rate of 10 mg/day for the treatment of socialphobia disorder and post-traumatic stress disorder; and in such anamount that the content of paroxetine is 20 mg/day for the treatment ofgeneralized anxiety disorder.

BEST MODE FOR CARRYING OUT THE INVENTION

The constitutions and operations of the present invention will beexplained in more detail with reference to the following examples.However, these examples are not to be construed as limiting the scope ofthe invention.

EXAMPLE 1

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in 20 mL of methanol while heating to 40° C. withshaking for 2 hours. The solvent was removed under reduced pressure, andthen the residue was dried under vacuum, yielding 2.2 g of solidparoxetine cholate as a white powder.

EXAMPLE 2

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in a mixed solvent of methanol (10 mL) and acetone(40 mL) while heating to 40° C. with shaking for 30 minutes. Thesolution was allowed to stand at room temperature for 24 hours to obtaina salt. The salt was filtered, and dried under vacuum to yield 2.0 g ofsolid paroxetine cholate as a white crystal.

EXAMPLE 3

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in 10 mL of methanol while heating to 40° C. withshaking for one hour. The solution was slowly added dropwise to 100 mLof ethyl ether to precipitate a solid, stirred at 0° C. for 3 hours, andfiltered. The filtered residue was washed with 30 mL of ethyl ether, anddried under vacuum to yield 1.89 g of solid paroxetine cholate as alight gray powder.

EXAMPLE 4

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in a mixed solvent of ethanol (20 mL) and isopropylacetate (30 mL) while heating to 50° C. with shaking for 2 hours. Thesolution was allowed to stand at −20° C. for 48 hours, filtered, anddried under vacuum to yield 1.9 g of solid paroxetine cholate as a lightgray powder.

EXAMPLE 5

1.0 g of oily paroxetine free base and 1.24 g of cholic acid weresuspended in 50 mL of isopropanol. After the suspension was refluxedwith stirring for 3 hours, it was slowly stirred at 25° C. for 2 hours,filtered and followed by drying under vacuum, yielding 2.15 g of solidparoxetine cholate as a white crystal.

EXAMPLE 6

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in a mixed solvent of purified water (5 mL) andmethanol (30 mL) with stirring for 2 hours. The solution was allowed tostand at 0° C. for 48 hours, filtered, and dried under vacuum to yield1.8 g of solid paroxetine cholate as a white powder.

EXAMPLE 7

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in a mixed solvent of ethanol (30 mL) anddichloromethane (50 mL) while heating to 50° C. with shaking for 3hours. After the solution was distilled under reduced pressure to removethe dichloromethane, it was allowed to stand at 25° C. for 8 hours,filtered, and dried under vacuum to yield 1.94 g of solid paroxetinecholate as a white crystal.

EXAMPLE 8

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in 10 mL of N,N-dimethylformamide with stirring for10 minutes. The solution was slowly added dropwise to 100 mL ofisopropyl acetate to precipitate a solid, stirred at 0° C. for 3 hours,and filtered. The filtered residue was washed with 30 mL of ethyl ether,and dried under vacuum to yield 1.84 g of solid paroxetine cholate as alight gray powder.

EXAMPLE 9

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in 10 mL of N,N-dimethylacetamide while heating to40° C. with shaking for 20 minutes. The solution was slowly addeddropwise to 100 mL of ethyl ether to precipitate a solid, stirred at 0°C. for 3 hours, and filtered. The filtered residue was washed with 30 mLof ethyl ether, and dried under vacuum to yield 1.75 g of solidparoxetine cholate as a light gray powder.

EXAMPLE 10

1.0 g of oily paroxetine free base and 1.24 g of cholic acid werecompletely dissolved in 10 mL of dimethylsulfoxide with stirring for 5minutes. The solution was slowly added dropwise to 100 mL of purifiedwater to precipitate a solid, stirred at 0° C. for 3 hours, andfiltered. The filtered residue was washed with 30 mL of ethyl ether, anddried under vacuum to give 1.7 g of solid paroxetine cholate as a whitepowder.

EXAMPLE 11

1.0 g of oily paroxetine free base and 1.19 g of deoxycholic acid werecompletely dissolved in 10 mL of methyl ethyl ketone while heating to40° C. with shaking for one hour. The solution was left to stand at −20°C.˜0° C. for 24 hours to precipitate a crystal, and filtered. Thefiltered residue was washed with cold methanol at 0° C. or below, anddried under vacuum to give 2.1 g of solid paroxetine deoxycholate as awhite powder.

EXAMPLE 12

0.8 g of oily paroxetine free base and 1.13 g of glycocholic acid werecompletely dissolved in 20 mL of ethanol while heating to 40° C. withshaking for 3 hours. After the solution was concentrated under reducedpressure until about 5 mL of the solvent was left, it was allowed tostand at −20° C.˜0° C. for 24 hours to precipitate a crystal, followedby filtration. The filtered residue was washed with cold methanol at 0°C. or less, and dried under vacuum to give 1.6 g of solid paroxetineglycocholate as a light gray powder.

EXAMPLE 13

0.8 g of oily paroxetine free base and 1.31 g of taurocholic acid werecompletely dissolved in a mixed solvent of purified water (5 mL) andethanol (20 mL) while heating to 40° C. with shaking for one hour. Afterthe solution was concentrated under reduced pressure until about 5 mL ofthe solvent was left, it was allowed to stand at −20° C.˜0° C. for 24hours to precipitate a crystal, followed by filtration. The filteredresidue was washed with cold methanol at 0° C. or less, and dried undervacuum to give 1.8 g of solid paroxetine taurocholate as a light graypowder.

EXAMPLES 14–17

After paroxetine cholate, dicalcium phosphate, microcrystallinecellulose, and sodium croscarmellose were mixed together in compliancewith the compositions of Examples 14 and 15 indicated in Table 1 below,each of the mixtures was passed through a 30 mesh standard sieve.Thereafter, magnesium stearate in the amounts shown in Table 1 was addedto the respective sieved mixtures and further mixed, and the finalmixture was compressed into tablets by common techniques.

Meanwhile, after paroxetine cholate, dicalcium phosphate, aspartame, andorange flavor powder were mixed together in compliance with thecompositions of Examples 16 and 17 indicated in Table 1, each of themixtures was passed through a 30 mesh standard sieve. Thereafter,Pharmagum S and magnesium stearate in the amounts shown in Table 1 wereadded to the respective sieved mixtures and further mixed, and the finalmixture was compressed into tablets by common techniques. The tabletsfor oral administration could be taken or swallowed without water,leaving behind no bitter taste despite rapid disintegration in themouth.

TABLE 1 Pharmaceutical compositions of Examples 14–17 Example 14 Example15 Example 16 Example 17 Paroxetine 20.0 mg  30.0 mg  20.0 mg  30.0 mgCholate (as free (as free base) (as free base) (as free base) base)Dicalcium 80.0 mg 120.0 mg  40.0 mg  60.0 mg Phosphate (DCPA)Microcrystalline 50.0 mg  75.0 mg — — Cellulose Sod. 10.0 mg  15.0 mg —— croscarmellose Pharmagum S* — — 240.0 mg 360.0 mg Aspartame — —  0.2mg  0.3 mg Orange Flavor — —  0.5 mg  0.75 mg Powder Mg. Stearate  1.5mg  2.25 mg  1.5 mg  2.25 mg *Pharmagum S: Trade name of rapidlydisintegrating excipient commercially available from SPI Pharma.

EXAMPLES 18–21

After paroxetine glycocholate, microcrystalline cellulose, sodiumcroscarmellose, and L-hydroxypropyl cellulose were mixed together incompliance with the compositions of Examples 18 and 19 indicated inTable 2 below, each of the mixtures was passed through a 30 meshstandard sieve and kneaded with a binding solution prepared bydissolving Povidone K-30 in the amount shown in Table 2 in water. Eachof the kneaded mixtures was dried in a dry oven at 40° C. until the lossof drying (LOD) was 2% or less, and passed through an 18 mesh standardsieve to obtain granular particles having a size of 18 mesh or less.Magnesium stearate in the amounts shown in Table 2 was added to therespective granular particles and further mixed, and the final mixturewas compressed into tablets by common techniques.

Meanwhile, after paroxetine glycocholate and microcrystalline cellulosewere mixed with each other in compliance with the compositions ofExamples 20 and 21 indicated in Table 2, each of the mixtures was passedthrough a 30 mesh standard sieve and kneaded with a binding solutionprepared by dissolving Povidone K-30 in water in the amount shown inTable 2.

Each of the kneaded mixtures was dried in a dry oven at 40° C. until theloss of drying (LOD) was 2% or less, and passed through a 24 meshstandard sieve to obtain granular particles having a size of 24 mesh orless. Pharmaburst X, grape flavor powder, citric acid powder having asize of 30 mesh or less, and magnesium stearate in the amounts shown inTable 2 was added to the respective granular particles and furthermixed, and the final mixture was compressed into tablets by commontechniques. The tablets for oral administration could be taken orswallowed without water, leaving behind no bitter taste despite rapiddisintegration in the mouth.

TABLE 2 Pharmaceutical compositions of Examples 18–21 Example 18 Example19 Example 20 Example 21 Paroxetine 20.0 mg 30.0 mg  20.0 mg  30.0 mgGlycocholate (as free (as free base) (as free base) (as free base) base)Povidone K-30 10.0 mg 15.0 mg  15.0 mg  22.5 mg Microcrystalline 100.0mg  150.0 mg  100.0 mg 150.0 mg Cellulose Sod. 10.0 mg 15.0 mg — —Croscarmellose L-Hydroxypropyl 30.0 mg 40.0 mg — — Cellulose PharmaburstX* — — 240.0 mg 320.0 mg Grape Flavor — —  1.0 mg  1.5 mg Powder CitricAcid — —  1.0 mg  1.5 mg Mg. Stearate  1.5 mg 2.25 mg  1.5 mg  2.25 mg*Pharmaburst X: Trade name of rapidly disintegrating excipientcommercially available from SPI Pharma.

EXAMPLES 22–25

After paroxetine taurocholate, microcrystalline cellulose, sodiumcroscarmellose, and L-hydroxypropyl cellulose were mixed together incompliance with the compositions of Examples 22 and 23 indicated inTable 3 below, each of the mixtures was passed through a 30 meshstandard sieve and kneaded with a binding solution prepared bydissolving Povidone K-30 in water in the amount shown in Table 3. Eachof the kneaded mixtures was dried in a dry oven at 40° C. until the lossof drying (LOD) was 2% or less, and passed through an 18 mesh standardsieve to obtain granular particles having a size of 18 mesh or less.Magnesium stearate in the amounts shown in Table 3 was added to therespective granular particles and further mixed, and the final mixturewas compressed into tablets by common techniques.

Meanwhile, after paroxetine taurocholate and microcrystalline cellulosewere mixed with each other in compliance with the compositions ofExamples 24 and 25 indicated in Table 3, each of the mixtures was passedthrough a 30 mesh standard sieve and kneaded with a binding solutionprepared by dissolving Povidone K-30 in water in the amount shown inTable 3.

Each of the kneaded mixtures was dried in a dry oven at 40° C. until theloss of drying (LOD) was 2% or less, and passed through a 24 meshstandard sieve to obtain granular particles having a size of 24 mesh orless. Pharmaburst X, grape flavor powder, citric acid powder having asize of 30 mesh or less, and magnesium stearate in the amounts shown inTable 3 were added to the respective granular particles and furthermixed, and the final mixture was compressed into tablets by commontechniques. The tablets for oral administration could be taken orswallowed without water, leaving behind no bitter taste despite rapiddisintegration in the mouth.

TABLE 3 Pharmaceutical compositions of Examples 22–25 Example 22 Example23 Example 24 Example 25 Paroxetine 20.0 mg 30.0 mg  20.0 mg 30.0 mgTaurocholate (as free (as free base) (as free base) (as free base) base)Povidone K-30 10.0 mg 15.0 mg  16.0 mg 23.0 mg Microcrystalline 90.0 mg130.0 mg  110.0 mg 150.0 mg  Cellulose Sod. 15.0 mg 20.0 mg — —Croscarmellose L-Hydroxypropyl 30.0 mg 40.0 mg — — Cellulose PharmaburstX* — — 260.0 mg 340.0 mg  Grape Flavor — —  2.0 mg  2.5 mg Powder CitricAcid — —  1.0 mg  1.5 mg Mg. Stearate  1.5 mg 2.25 mg  1.5 mg 2.25 mg*Pharmaburst X: Trade name of rapidly disintegrating excipientcommercially available from SPI Pharma.

EXAMPLES 26 AND 27

After paroxetine cholate, dicalcium phosphate, microcrystallinecellulose, and sodium croscarmellose were mixed together in compliancewith the compositions of Examples 14 and 15 indicated in Table 1 above,each of the mixtures was passed through a 30 mesh standard sieve forexamples 26 and 27, respectively. Thereafter, magnesium stearate in theamounts shown in Table 1 was added to the respective sieved mixtures andfurther mixed, and the final mixture was filled into a #2 capsule bycommon techniques.

EXAMPLES 28 AND 29

After paroxetine glycocholate, microcrystalline cellulose, sodiumcroscarmellose, and L-hydroxypropyl cellulose were mixed together incompliance with the compositions of Examples 18 and 19 indicated inTable 2 above, each of the mixtures was passed through a 30 meshstandard sieve and kneaded with a binding solution prepared bydissolving Povidone K-30 in water in the amount shown in Table 2 above,for Examples 28 and 29, respectively. Each of the kneaded mixtures wasdried in a dry oven at 40° C. until the loss of drying (LOD) was 2% orless, and passed through an 18 mesh standard sieve to obtain granularparticles having a size of 18 mesh or less. Magnesium stearate in theamounts shown in Table 2 was added to the respective granular particlesand further mixed, and the final mixture was filled into a #2 capsule bycommon techniques.

EXAMPLES 30 AND 31

Each 1.51 g and 3.02 g of paroxetine hydrochloride salt washomogeneously mixed with 1.65 g of cholic acid, and then kneaded witheach 0.7 g and 1 g_of a binding solution prepared by dissolving PovidoneK-30 in ethanol in the amount of 30 w/v %, for Examples 30 and 31,respectively. The kneaded mixture was dried in a dry oven at 40° C.until the loss of drying (LOD) was 2% or less, and passed through a 30mesh standard sieve to obtain granular particles having a size of 30mesh or less. The final granular particle was used as paroxetinecompositions containing cholic acid.

EXAMPLES 32 AND 33

After each amount corresponding to 20 mg of the paroxetine free base wassampled from the respective paroxetine compositions prepared in Examples30 and 31, each of the samples was mixed with dicalcium phosphate,microcrystalline cellulose and sodium croscarmellose in compliance withthe composition of Example 14 indicated in Table 1 above and filteredthrough a 30 mesh standard sieve for Examples 32 and 33, respectively.Magnesium stearate in the amounts shown in Example 14 was added to therespective sieved mixtures and further mixed, and the final mixture wascompressed into tablets by common techniques.

EXAMPLE 34

0.5 g of ethanol was added to 1.33 g of paroxetine free base to obtain aslurry, and then 3.3 g of cholic acid was added thereto. The resultingmixture was kneaded, dried in a dry oven at 40° C. until the loss ofdrying (LOD) was 2% or less, and passed through a 30 mesh standard sieveto obtain granular particles having a size of 30 mesh or less, which wasused as a paroxetine composition containing cholic acid.

EXAMPLE 35

After the amount corresponding to 20 mg of paroxetine free base wassampled from the paroxetine composition prepared in Example 34, thesample was mixed with dicalcium phosphate, aspartame, and orange flavorpowder in compliance with the composition of Example 16 indicated inTable 1 above, and filtered through a 30 mesh standard sieve. PharmagumS and magnesium stearate in the amounts shown in Example 16 were addedto the sieved mixture and further mixed, and the final mixture wascompressed into tablets by common techniques. The tablets for oraladministration could be eaten and swallowed without water, leavingbehind no bitter taste despite rapid disintegration in the mouth.

COMPARATIVE EXAMPLE 1 Taste Comparison

After 5 mg of drug in solid state from each of the drugs shown in Table4 was sampled without using any excipient, water or other solvents, thetaste of the drugs was evaluated by three panelists over a period of 10minutes in the mouth. Paroxetine initially leaves a characteristicbitter taste even in small amounts, and then causes irritating painalong with an intolerable bitter taste with the passage of time.

According to the experimental results (Table 4), other paroxetine saltsexcept paroxetine cholate and paroxetine glycocholate initially left abitter taste and caused irritating pain along with a bitter taste withthe passage of time. Particularly, currently marketed or approvedparoxetine hydrochloride and paroxetine methanesulfonate left a bittertaste inherent in paroxetine and incurred a strong rejection by thepanelists. In contrast, the paroxetine cholate and paroxetineglycocholate of the present invention removed the bitter taste and paininherent in paroxetine and incurred no rejection by the panelists. Inaddition, it was confirmed that reduction of the characteristic tasteand pain of paroxetine could also be achieved by only blendingparoxetine with cholic acid. Accordingly, the paroxetine cholate orcholic acid derivative salt and the composition comprising paroxetineand cholic acid or derivative thereof of the present invention aresuitable as orally disintegrating tablets for anti-depressants.

TABLE 4 Initial taste Later taste (within one min.) (after one min.)Paroxetine cholate No taste No pain Mixture of paroxetine and Slightlybitter taste No pain cholic acid (1:1, molar ratio) Paroxetineglycocholate No taste No pain Paroxetine glucuronate Bitter tasteIrritating pain caused Paroxetine HCl Very bitter taste Irritating paincaused Paroxetine Very bitter taste Irritating pain causedmethanesulfonate Paroxetine tartarate Very bitter taste Irritating paincaused Paroxetine napsylate Very bitter taste Irritating pain caused

COMPARATIVE EXAMPLE 2 Stability Comparison

Each of the drugs shown in Table 5 was completely dissolved in a 0.3%hydrogen peroxide solution at a concentration of 1 mg/mL. While storageunder stressed conditions at 80° C., changes in the contents of thedrugs were monitored. The 0.3% hydrogen peroxide solution is a solutioncommonly used to quickly determine the stability of drugs and providesstressed conditions for artificial acceleration of the oxidation of thedrugs. The content analysis was conducted by HPLC in accordance with theparoxetine content analysis defined in USP.

HPLC analysis indicated that paroxetine cholate and paroxetineglycocholate are highly stable when compared to other paroxetine salts.Particularly, the contents of currently marketed or approved paroxetinehydrochloride and paroxetine methanesulfonate rapidly decreased to 54%or below for 48 hours, and to about 15% or below within 120 hours afterstorage. The results indicate that such drugs cause nearly complete lossof the drugs within 120 hours. In contrast, the salts of the presentinvention were maintained at a content level of 89% or more for 48 hoursand 54% or more for 120 hours after storage. Accordingly, the salts ofthe present invention turned out to be surprisingly stable. In addition,it was confirmed that the improvement in stability could also beachieved by only blending paroxetine with cholic acid.

TABLE 5 Stability comparison of paroxetine salts under severe conditions(chamber at 80° C., 0.3% hydrogen peroxide) 144 Initial 24 hrs 48 hrs 72hrs 120 hrs hrs Paroxetine 100.0% 98.2% 92.4% — 66.3% — cholate Mixtureof 100.0% 97.4% 90.3% — 63.9% — paroxetine and cholic acid (1:1, molarratio) Paroxetine 100.0% 96.8% 89.6% — 54.3% — glycocholate Paroxetine100.0% 92.8% 59.0% — 12.3% — glucuronate Paroxetine HCl 100.0% 84.5%53.8% — 13.4% — Paroxetine 100.0% 74.4% 31.8% 16.6% — — methanesulfonateParoxetine 100.0% 81.3% — 28.3% — 4.8% tartarate Paroxetine 100.0% 60.4%— 16.1% — 3.5% napsylate

INDUSTRIAL APPLICABILITY

As apparent from the above description, in the novel paroxetine saltsand paroxetine composition of the present invention, the bitter tasteinherent in paroxetine is completely removed not by a way hiding thebitter taste with complexes using ion-exchange resins, clathrates usingcyclodextrins, coatings using polymers, other material having an intenseflavor and taste, and so on, like conventional techniques, but by a wayforming paroxetine salt with cholic acid or its derivatives having aslightly bitter taste. That is, this way of the present invention is tocompletely remove the taste of paroxetine itself without modification ofthe taste. Thus it surprisingly eliminates the characteristic taste andpain associated with paroxetine.

In addition, unlike the glycyrrhyzinic acid and glycyrrhyzinate saltsdisclosed in PCT Publications WO 03/013470 and WO 03/013529 in which theintense flavor and taste of liquorice induce changes in the taste ofparoxetine, the salts of the present invention uses cholic acid or itsderivatives having a slightly bitter taste to completely remove thebitter taste inherent in paroxetine without any taste changes.

Furthermore, the paroxetine cholate and paroxetine cholic acidderivative salts of the present invention have excellent stabilityagainst oxidation, which is considered to be a main factor decreasingthe content of drugs in the evaluation of drug stability, as compared toother paroxetine salts.

Therefore, the paroxetine cholate and paroxetine cholic acid derivativesalts of the present invention are suitable as agents for oraladministration swallowing it without water, particularly solidanti-depressants, and can be applied to liquid preparations due to theirexcellent stability.

Moreover, no taste and superior stability of paroxetine can be achievednot only through the formation of the paroxetine salt but also throughblending of paroxetine with cholic acid or a derivative thereof.

Although the preferred embodiments of the present invention have beendisclosed for illustrative purposes, those skilled in the art willappreciate that various modifications, additions and substitutions arepossible, without departing from the scope and spirit of the inventionas disclosed in the accompanying claims.

1. A paroxetine cholate or cholic acid derivative salt thereof, whereinthe cholic acid and its derivative are represented by Formula 1:

wherein R₁, R₂, and R₃ are independently hydrogen or a hydroxy group;and X is —OH, —ONa, —NH—(CH₂)_(n)—SO₃H, —NH—(CH₂)_(n)—SO₃Na,—NH—(CH₂)_(n)—SO₃K, —NH—(CH₂)_(n)—CO₂H, —NH—(CH₂)_(n)—CO₂Na, or—NH—(CH₂)_(n)—CO₂K (in which n is an integer between 1 and 3), orFormula 2:

wherein X is as defined in Formula
 1. 2. The salt according to claim 1,wherein the salt is a paroxetine cholate salt.
 3. The salt according toclaim 1 or 2, wherein the paroxetine salt is in crystalline form.
 4. Thesalt according to claim 1 or 2, wherein the paroxetine salt is innon-crystalline form.
 5. A pharmaceutical composition comprising theparoxetine salt according to claim 1 or 2 and a pharmaceuticallyacceptable excipient.
 6. The composition according to claim 5, whereinthe composition is formulated into an oral preparation for swallowingwithout water.
 7. A composition comprising paroxetine and cholic acid ora derivative thereof, wherein the cholic acid and its derivative arerepresented by Formula 1:

wherein R₁, R₂, and R₃ are independently hydrogen or a hydroxy group;and X is —OH, —ONa, —NH—(CH₂)_(n)—SO₃H, —NH—(CH₂)_(n)—SO₃Na,—NH—(CH₂)_(n)—SO₃K, —NH—(CH₂)_(n)—CO₂H, —NH—(CH₂)_(n)—CO₂Na, or—NH—(CH₂)_(n)—CO₂K (in which n is an integer between 1 and 3), orFormula 2:

wherein X is as defined in Formula
 1. 8. The composition according toclaim 7, wherein the molar ratio of the cholic acid or its derivative tothe paroxetine is between 0.5:1 and 2:1.
 9. The composition according toclaim 7 or 8, wherein the composition is prepared by uniformly blendingparoxetine and cholic acid or a derivative thereof in water or anorganic solvent, followed by drying.
 10. A pharmaceutical compositioncomprising the composition according to claim 7 or 8 and apharmaceutically acceptable excipient.
 11. The pharmaceuticalcomposition according to claim 9, further comprising a pharmaceuticallyacceptable excipient.
 12. The pharmaceutical composition according toclaim 10, wherein the composition is formulated into an oral preparationfor swallowing without water.
 13. The pharmaceutical compositionaccording to claim 11, wherein the composition is formulated into anoral preparation for swallowing without water.
 14. A method for treatingdepressive disorder, comprising administering a therapeuticallyeffective amount of the paroxetine cholate or cholic acid derivativesalt according to claim 1 to a human in need of such treatment.
 15. Amethod for treating depressive disorder, comprising administering atherapeutically effective amount of the composition according to claim 7to a human in need of such treatment.